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A Clinical Trial of the P-Glycoprotein Antagonist, Tariquidar (XR9576), in Combination With Docetaxel in Patients With Lung, Ovarian, Renal and Cervical Cancer: Analysis of the Interaction Between Tariquidar and Docetaxel

Trial Information

A Clinical Trial of the P-Glycoprotein Antagonist, Tariquidar (XR9576), in Combination With Docetaxel in Patients With Lung, Ovarian, Renal and Cervical Cancer: Analysis of the Interaction Between Tariquidar and Docetaxel

Intrinsic and acquired drug resistance remain major obstacles in the treatment of cancer.
Accumulating evidence indicates that in some malignancies P-glycoprotein (Pgp) can confer
resistance, and that its reversal can improve therapeutic outcome. Clinical trials
investigating Pgp antagonists have been hampered by the occurrence of unpredictable
pharmacokinetic interactions, which have required dose reductions of the chemotherapeutic
agents to avert excessive toxicity. Tariquidar (XR9576) is a new Pgp antagonist that is more
potent and has prolonged activity. Phase I trials with paclitaxel, vinorelbine, and
docetaxel have demonstrated that tariquidar (XR9576) has minimal pharmacokinetic
interactions while surrogate studies have confirmed in vivo inhibition of Pgp-mediated drug
transport.This study seeks to determine the pharmacokinetic interaction, if any between
docetaxel and tariquidar and to evaluate the potential for activity in lung, ovarian,
primary peritoneal, fallopian tube and cervical cancers. Renal cell cancer has been added in
a 3/1/06 amendment. The secondary goal is to evaluate the impact of tariquidar on uptake of
(99m)Tc-sestamibi in recurrent or metastatic tumors of patients with lung, ovarian, renal or
cervical cancer.

Inclusion Criteria:

- Patients must fulfill all of the following criteria to be eligible for study
admission:

- Age greater than or equal to 18 years.

- Histologic or cytologic confirmation of lung, cervical, or ovarian cancer, following
at least one standard treatment regimen, and for which there is no known standard
therapy capable of extending life expectancy. Female patients with primary papillary
carcinoma of the peritoneum and fallopian tube cancers will be included in the latter
group, as the disease entities are closely associated with epithelial ovarian
carcinoma, can be difficult to distinguish, have a similar epithelial origin, and are
treated in an identical manner.

- Histologic or cytologic confirmation of renal cell carcinoma (clear cell, type 1 and
type II papillary chromophobe, collecting duct and medullary). Patients should have
received either sunitinib or sorafenib, unless deemed ineligible for treatment with
either agent. In addition,patient should either: (a) have received IL-2; (b) have
been evaluated for therapy with Interleukin-2 (IL- 2) and deemed to be ineligible; or
(c) have been evaluated for therapy with IL2 and refused treatment.

- Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2

- Life expectancy of 3 months or greater.

- Suitable candidate for receiving planned therapy as evidenced by screening laboratory
assessments hematologic, renal hepatic, and metabolic functions, platelet count
greater than or equal to 90,000/mL, absolute granulocyte count(AGC) greater than or
equal to 1,500/mL, serum creatinine greater than or equal to 1,500/mL, serum creatine
less than or equal to 1.5 mg/dl )or if greater than 1.5 a measured 24 hour creatinine
clearance greater than or equal to 50 mL/min) and serum glutamic oxaloacetic
transaminase (SGOT) less than or equal to 2.5 x normal limit (NL) and bilirubin less
than or equal to 1.5 x NL (in patients with clinical evidence of Gilbert's
disease,less than or equal to 3 x NL).

- Patients must be greater than or equal to 4 weeks prior radiation or chemotherapy,
greater than 2 weeks from hormonal therapy; greater than 4 weeks from prior
experimental therapy; greater than 6 weeks from mitomycin C; and greater than 8 weeks
from prior UCN01 treatment.

- Willingness to sign a written consent form, and to comply with the protocol.

Exclusion Criteria:

- The following patient populations are not eligible for this study.

- Pregnant or nursing women are not eligible; women of childbearing age must agree to
use an effective method of contraception. Pregnant women are not eligible because of
teratogenic effects of chemotherapy.

- The presence of a second malignancy that has not received primary treatment or would
complicate the primary objective of this study.

- Patients who are poor medical risk because of active, uncontrolled infection or other
nonmalignant systemic disease.

- Human immunodeficiency virus (HIV) seropositive patients. Patients infected with the
HIV virus will be excluded from this trial because the effect of the combination of
tariquidar and docetaxel on HIV replication and/or the immune system is unknown and
potentially harmful.

- Patients receiving agents which have major interactions with the cytochrome P450 3A4
(CYP3A4)drug metabolizing system and which cannot be discontinued may not be included
in the trial.

- Untreated brain metastases (or local treatment of brain metastases within the last 6
months) due to the poor prognosis of these patients and difficulty ascertaining the
cause of neurologic toxicities.

Type of Study:

Study Design:

Outcome Measure:

Geometric Mean of Maximum Concentration of the Drug (Cmax)

Outcome Description:

In the first cycle patients were to receive docetaxel on days 1 and 8 and to be randomized to receive tariquidar on either day 1 or 8. Thus pharmacokinetic data with and without tariquidar can be compared.

Outcome Time Frame:

24 hours

Safety Issue:

No

Principal Investigator

Susan E Bates, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

NCI, NIH

Authority:

United States: Federal Government

Study ID:

030284

NCT ID:

NCT00069160

Start Date:

September 2003

Completion Date:

December 2009

Related Keywords:

Lung Neoplasms

Ovarian Neoplasms

Cervix Neoplasms

Renal Neoplasms

Pharmacokinetics

Pharmacodynamics

Multidrug Resistance Reversal

Molecular Target

P-Glycoprotein Inhibition

Lung Cancer

Ovarian Cancer

Cervical Cancer

Renal Cancer

Neoplasms

Uterine Cervical Neoplasms

Kidney Neoplasms

Lung Neoplasms

Ovarian Neoplasms

Name

Location

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